Phase III study of maintenance gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC).

Abstract

Background: The use of single agent cytotoxic or targeted agent as maintenance following combination therapy represents a useful strategy to improve patient outcomes in advanced stage NSCLC. An earlier study with gemcitabine as maintenance therapy demonstrated improved time to progression (TTP) compared to BSC (6.6 mos. vs 5.0 mos., p < 0.001) (Brodowicz et al, Lung Cancer, 2006; 52:155-163). Based on this, we conducted a randomized phase III study to compare G + BSC versus BSC as maintenance therapy for patients with advanced NSCLC. Methods: Patients with stage IIIB (wet)/IV NSCLC were initially treated with gemcitabine (1,000 mg/m 2 on day 1 and 8) and carboplatin (AUC = 5 mg/mL.min on d 1) every 3 weeks for 4 cycles. Subsequently, patients with CR/PR or SD were randomized 1:1 to receive maintenance G (1,000 mg/m 2 on d 1 and 8), every 3 weeks with BSC or BSC alone until disease progression. The primary endpoint was the comparison of overall survival between the two arms and the secondary endpoint was progression free survival (PFS). Results: 519 patients were enrolled (median age-67 years, stage IV disease-86%, ECOG performance status 0/1-75%). With G-Cb, the RR was 28% (CR-1.2%, PR-26.8%), and 37% had SD. Following 4 cycles of G-Cb, 255 non-progressors were randomized to receive G + BSC (n = 128) or BSC (n = 127). The median PFS was 3.9 m (95% CI:3.3, 5.6) for G + BSC and 3.8 m (95% CI: 2.6, 5.5) for BSC. Median survival was 8.0 m (95% CI: 6.0, 10.2) for G+ BSC and 9.3 m (95% CI: 7.7, 12.7) for BSC. The differences in survival between the two arms were not statistically significant (HR = 0.97 [95% CI: 0.72, 1.30], p = 0.84). Maintenance therapy was tolerated well despite a higher incidence of grade 3/4 toxicity (anemia 9.4% vs. 2.4%; neutropenia 13.3% vs. 1.6%; thrombocytopenia 9.4% vs. 1.4%; and fatigue 3.9% vs. 1.6%). Conclusions: The use of gemcitabine as maintenance therapy failed to improve survival following G-Cb in patients with advanced NSCLC.

Personalized Choice of Maintenance Therapies in Non-Small-Cell Lung Cancer

“…In a similar trial, Belani et al 20 enrolled 519 patients and randomized 255 nonprogressors to receive gemcitabine plus bsc or bsc alone. The median progression-free survival (pfs) was 3.9 months for gemcitabine plus bsc and 3.8 months for bsc alone.…”

Effectiveness of maintenance treatments for nonsmall cell lung cancer

“…The use of gemcitabine for continuation maintenance therapy for advanced NSCLC has been studied in three randomized controlled trials, [10][11][12] two of which have demonstrated an improvement in progression-free survival on the order of 1-2 months. 10,11 No trials to date have shown a survival benefit for the continuation of gemcitabine beyond its use in a first-line platinum doublet.…”

“…Although most of the studies report acceptable toxicity in the maintenance arm, many report some increase in grade 3 and 4 toxicities in patients receiving maintenance therapy. 11,12,16,17,[20][21][22]27 Maintenance therapy with the EGFR tyrosine kinase inhibitors appears to have the least toxicity, with the exception of the expected rash and diarrhea. When toxicity and quality of life were analyzed in the meta-analysis by Soon et al, adverse events were more common in the maintenance patients, and two of the seven trials that reported health-related quality of life outcomes did show trends toward a worse quality of life by extending chemotherapy.…”

“…12 It was limited by slow accrual, failing to reach the projected 238 target events over 6 years. Furthermore, 25% of the patients had a performance status of 2 or greater.…”

“…Furthermore, 25% of the patients had a performance status of 2 or greater. 6,12 In total, 519 patients with advanced NSCLC were enrolled and treated with gemcitabine 1000 mg/m 2 on days 1 and 8 and carboplatin AUC 5 every 3 weeks for four cycles. Two hundred and fifty-five patients (49%) did not have disease progression and were subsequently randomized to maintenance gemcitabine plus best supportive care (n = 128) vs best supportive care alone (n = 127).…”